Multidrug-resistant malaria parasite Plasmodium falciparum is a major contributing factor to the global resurgence of malaria. With the failing of many antimalarial drugs, most malaria- endemic countries have adopted artemisinin-based combination therapy (ACT) to treat falciparum malaria. Although these are the only class of antimalarial drugs to which there is no confirmed clinical resistance, the reports of artemisinin treatment failures in many regions of the world are of great concern. The exact mode of action of artemisinins and the mechanism of resistance are poorly understood, making resistance surveillance in areas of artemisinin deployment very difficult. Here, we propose to use laboratory selected artemisinin-resistant parasite clones for elucidating the mechanism of artemisinin resistance. Using recently developed genome-wide analysis tools, we propose to 1) identify single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) associated with the resistant parasites using high-density tiling arrays;and 2) filter out the sequence polymorphisms that might be responsible for the observed resistance to artemisinin using genome-wide expression microarray and quantitative proteomics. These high-throughput approaches will allow cross examination and identification of candidate polymorphisms that can be validated in future studies. PUBLIC HEALTH RELEVANCE: In response to the escalating problem of drug resistance in malaria control, artemisinin-based combinatory therapy (ACT) is being adopted by many malaria-endemic nations. This study aims at better understanding the resistance mechanism using laboratory selected artemisinin-resistant lines. The results from this study may allow us to design and implement countermeasures to closely monitor and prevent resistance development to artemisinins in field parasite populations.